ORCID Profile
0000-0001-8802-2906
Current Organisation
RIKEN Centre for Integrative Medical Research (IMS)
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Publisher: Elsevier BV
Date: 2015
DOI: 10.1038/MTM.2015.15
Publisher: Cold Spring Harbor Laboratory
Date: 19-01-2021
DOI: 10.1101/2021.01.19.427209
Abstract: Single-cell RNA-sequencing analysis to quantify RNA molecules in in idual cells has become popular owing to the large amount of information one can obtain from each experiment. We have developed UniverSC ( inoda-lab/universc ), a universal single-cell processing tool that supports any UMI-based platform. Our command-line tool enables consistent and comprehensive integration, comparison, and evaluation across data generated from a wide range of platforms.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-05-2015
DOI: 10.1002/HEP.27842
Abstract: Liver‐targeted gene therapy based on recombinant adeno‐associated viral vectors (rAAV) shows promising therapeutic efficacy in animal models and adult‐focused clinical trials. This promise, however, is not directly translatable to the growing liver, where high rates of hepatocellular proliferation are accompanied by loss of episomal rAAV genomes and subsequently a loss in therapeutic efficacy. We have developed a hybrid rAAV/ piggyBac transposon vector system combining the highly efficient liver‐targeting properties of rAAV with stable piggyBac ‐mediated transposition of the transgene into the hepatocyte genome. Transposition efficiency was first tested using an enhanced green fluorescent protein expression cassette following delivery to newborn wild‐type mice, with a 20‐fold increase in stably gene‐modified hepatocytes observed 4 weeks posttreatment compared to traditional rAAV gene delivery. We next modeled the therapeutic potential of the system in the context of severe urea cycle defects. A single treatment in the perinatal period was sufficient to confer robust and stable phenotype correction in the ornithine transcarbamylase–deficient Spfash mouse and the neonatal lethal argininosuccinate synthetase knockout mouse. Finally, transposon integration patterns were analyzed, revealing 127,386 unique integration sites which conformed to previously published piggyBac data. Conclusion : Using a hybrid rAAV/ piggyBac transposon vector system, we achieved stable therapeutic protection in two urea cycle defect mouse models a clinically conceivable early application of this technology in the management of severe urea cycle defects could be as a bridging therapy while awaiting liver transplantation further improvement of the system will result from the development of highly human liver‐tropic capsids, the use of alternative strategies to achieve transient transposase expression, and engineered refinements in the safety profile of piggyBac transposase‐mediated integration. (H epatology 2015 :417–428
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2021
DOI: 10.1101/2021.03.02.433636
Abstract: Pancreatic islet β-cells are factories for insulin production however ectopic expression of insulin is also well recognized. The gallbladder is a next-door neighbour to the developing pancreas. Here, we wanted to understand if gallbladders contain functional insulin-producing cells. We compared developing and adult mouse as well as human gallbladder epithelial cells and islets using immunohistochemistry, flow cytometry, ELISAs, RNA-sequencing, real-time PCR, chromatin immunoprecipitation and functional studies. We demonstrate that the epithelial lining of developing, as well as adult mouse and human gallbladders naturally contain interspersed cells that retain the capacity to actively transcribe, translate, package, and release insulin. We show for the first time that human gallbladders also contain functional insulin-secreting cells with the potential to naturally respond to glucose in vitro and in situ . Notably, in a NOD mouse model of type 1 diabetes, we observed that insulin-producing cells in the gallbladder are not targeted by autoimmune cells. Conclusion: In summary, our biochemical, transcriptomic, and functional data in human gallbladder epithelial cells collectively demonstrate their potential for insulin-production under pathophysiological conditions, and open newer areas for type 1 diabetes research and therapy. Developing pancreas and gallbladder are next-door neighbours and share similar developmental pathways. Human Gallbladder-derived progenitor cells were shown to differentiate into insulin-producing cells. Gallbladder epithelium contains interspersed cells that can transcribe, translate, package and secrete insulin. Insulin-producing cells in the gallbladder are not destroyed by immune cells in an animal model of type 1 diabetes (T1D). Our studies demonstrating the absence of insulin splice variants in human gallbladder cells, and higher splice forms in human islets, suggest a potential mechanism (via defective ribosomal products) in escaping islet autoimmunity. Deciphering mechanisms of protection of insulin-producing cells from immune cells in the gallbladder could help in developing strategies to prevent islet autoimmunity in T1D.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2016
DOI: 10.1038/SREP28965
Abstract: Germline endogenous viral elements (EVEs) genetically preserve viral nucleotide sequences useful to the study of viral evolution, gene mutation, and the phylogenetic relationships among host organisms. Here, we describe a lineage-specific, adeno-associated virus (AAV)-derived endogenous viral element (mAAV-EVE1) found within the germline of numerous closely related marsupial species. Molecular screening of a marsupial DNA panel indicated that mAAV-EVE1 occurs specifically within the marsupial suborder Macropodiformes (present-day kangaroos, wallabies, and related macropodoids), to the exclusion of other Diprotodontian lineages. Orthologous mAAV-EVE1 locus sequences from sixteen macropodoid species, representing a speciation history spanning an estimated 30 million years, facilitated compilation of an inferred ancestral sequence that recapitulates the genome of an ancient marsupial AAV that circulated among Australian metatherian fauna sometime during the late Eocene to early Oligocene. In silico gene reconstruction and molecular modelling indicate remarkable conservation of viral structure over a geologic timescale. Characterisation of AAV-EVE loci among disparate species affords insight into AAV evolution and, in the case of macropodoid species, may offer an additional genetic basis for assignment of phylogenetic relationships among the Macropodoidea. From an applied perspective, the identified AAV “fossils” provide novel capsid sequences for use in translational research and clinical applications.
Location: Australia
No related grants have been discovered for Nicola Hetherington.